The First Total Syntheses of Ircinol A, Ircinal A, and Manzamines A and D.

TLDR: The application of the intramolecular vinylogous amide photoaddition/fragmentation/Mannich closure sequence that the authors have developed has been applied to the stereoselective synthesis of complex structural types including mesembrine and the aspidosperma alkaloids from simple precursors.

Abstract: In 1986, Higa, Jefford, and co-workers reported the isolation of a structurally novel polycyclic alkaloid, manzamine A, 1, from a sponge harvested near the coast of Okinawa.1 The unique structure of 1 consists of a β-carboline heterocycle attached to a novel pentacyclic diamine core containing both eight- and thirteen-membered rings on a pyrrolo[2,3-i]isoquinoline framework. The cytotoxic activity (IC50 = 0.07 µg/mL against P-388 mouse leukemia cells) and unique structure of 1 have stimulated considerable interest and activity directed toward the total synthesis of manzamine A which has not yet been successfully achieved to date.2 The intramolecular vinylogous amide photoaddition/fragmentation/Mannich closure sequence that we have developed has been applied to the stereoselective synthesis of complex structural types including mesembrine and the aspidosperma alkaloids from simple precursors.3 We have described the application of this methodology to the construction of the tetracyclic core of the manzamine alkaloids, in which the single stereocenter on the unsaturated eight-membered ring template 2 dictates all of the requisite stereochemical relationships embodied in 3, which represents the tetracyclic core of manzamine A.4 Outlined herein is the extension of these preliminary investigations to the first total synthesis of manzamine A.